Actinin-4 gene Amplification in Ovarian Cancer: A Candidate Oncogene Associated With Poor Patient Prognosis and Tumor Chemoresistance

Sohei Yamamoto; Hitoshi Tsuda; Kazufumi Honda; Kaoru Onozato; Masashi Takano; Seiichi Tamai; Issei Imoto; Johji Inazawa; Tesshi Yamada; Osamu Matsubara

Disclosures

Mod Pathol. 2009;22(4):499-507. 

In This Article

Abstract and Introduction

Abstract

Actinin-4, an isoform of non-muscular α-actinin, enhances cell motility by bundling the actin cytoskeleton. We previously reported a prognostic implication of high immunohistochemical expression of actinin-4 protein in ovarian cancers. Chromosomal gain or amplification of the 19q12-q13 region has been reported in ovarian cancer. We hypothesized that the actinin-4 (ACTN4) gene might be a target of the 19q12-q13 amplicon and play an essential role of ovarian cancer progression. In total, 136 advanced-stage ovarian cancers were investigated for the copy number of the ACTN4 gene on chromosome 19q13, using fluorescence in situ hybridization, and the correlation of the ACTN4 copy number with actinin-4 protein immunoreactivity and major clinicopathological factors was investigated. A higher copy number (≥4 copies) of the ACTN4 gene was detected in 29 (21%) cases and was highly associated with the intensity of actinin-4 immunoreactivity (P<0.0001), a high histological tumor grade (P=0.030), a clear-cell adenocarcinoma histology (P=0.012), resistance to first-line chemotherapies (P=0.028), and poor patient outcome (P=0.0011). Univariate analyses using the Cox regression model showed that a higher ACTN4 gene copy number was able to predict patient outcome more accurately than high actinin-4 immunoreactivity (relative risk: 2.48 vs 1.55). Multivariate analysis showed that a higher copy number of the ACTN4 gene and the degree of residual disease were independent prognostic factors for overall patient survival. The actinin-4 gene may be a target of the 19q amplicon, acting as a candidate oncogene, and serve as a predictor of poor outcome and tumor chemoresistance in patients with advanced-stage ovarian cancers.

Introduction

Epithelial ovarian cancer, accounting for 90% of all ovarian malignant tumors, is the leading cause of death among female genital malignancies.[1] Because of its insidious onset and lack of an effective early diagnostic test, up to 70% of cases are diagnosed at an advanced stage with extensive peritoneal dissemination and/or distant metastasis, resulting in an extremely poor prognosis.[1] Although ovarian cancer progression is a multistep process, involving local invasion, infiltration into vessels, survival in the circulation, extravasation, and growth at secondary sites, enhancement of cancer cell motility is also considered necessary.[2,3]

α-Actinin crosslinks the actin cytoskeleton, and two types of non-muscle α-actinins—actinin-1 and actinin-4—have been identified.[4,5] Actinin-1, localized at the ends of actin stress fibers, plays an important role in stabilizing cell adhesion through association with cell adhesion molecules such as integrin-β and α-catenin.[6,7] On the other hand, actinin-4 protein is highly concentrated at the leading edge of the cytoplasm of motile cells or actively moving structures such as cell surface ruffles, and is not localized to focal adhesion plaques or adherent junctions.[5,8,9,10]

In human cancer cells showing enhanced motility, the cytoplasmic expression levels of actinin-4 protein are significantly increased.[5,10] Recent studies have shown that cytoplasmic overexpression of actinin-4 is associated with various clinicopathological parameters in some human carcinomas: histologically invasive phenotypes of breast cancer,[5] lymph node metastasis of colorectal cancer,[10] poor prognosis of breast cancers, non-small cell lung cancers, and pancreatic cancer.[5,11,12]

Previously, using immunohistochemistry, we detected high actinin-4 protein expression in the cytoplasm in 52% (137 of 265 cases) of ovarian cancers, and this was significantly associated with a clinically advanced tumor stage, a serous adenocarcinoma histology, high-grade tumor histology, a high degree of residual tumor after initial surgery, and a poor patient outcome.[13] Multivariate analysis indicated that high actinin-4 expression can be a prognostic indicator that is independent of clinical stage and histologic subtype.[13] Therefore, as is the case in other solid cancers, the cytoplasmic accumulation of actinin-4 protein in ovarian cancer cells is suggested to be associated with tumor cell motility, invasiveness, and metastatic potential.

The actinin-4 (ACTN4) gene is localized to chromosome region 19q13.2 (http://www.ncbi.nlm.nih.gov/mapview/). In ovarian cancer, chromosomal gain or high copy-number amplification of 19q12-q13 in the form of a homogeneously staining region has been reported, and this region contains several candidate oncogenes such as cyclin E, AKT2, and SEI-1.[14,15,16,17,18] In the present study, we hypothesized that amplification of the ACTN4 gene might be a target of the 19q amplicon and play an essential role in ovarian cancer progression. Therefore, we investigated the copy number of the ACTN4 gene in chromosome 19q13.2 in 136 advanced-stage ovarian cancers using fluorescence in situ hybridization (FISH), and compared it with the intensity of actinin-4 immunoreactivity and major clinicopathological factors.

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